Five Psychiatric Disorders Share Genetic Link

Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia may share genetic risk factors, according to researchers at Massachusetts General Hospital. They say their work is the largest ever genetic study of psychiatric illness, and may help to one day reclassify these disorders on the basis of causes rather than descriptive syndromes.

To study the possibility of common genetic markers or nucleotide polymorphisms (SNPs) that might affect susceptibility to the five disorders, the Psychiatric Genomics Consortium (PGC) scanned the genome of 33,332 patients and 27,888 controls of European ancestry.

The team applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. They examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. They also performed pathway analyses to establish the biological associations underlying genetic overlap for the five disorders, and used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in postmortem brain-tissue samples.

Ultimately, they identified four risk loci that have significant and overlapping links with all five diseases—regions on chromosomes 3p21 and 10q24, and SNPs in two genes that make components of channels that regulate the flow of calcium in brain cells—CACNA1C and CACNB2.

Polygenic risk scores confirmed cross-disorder effects, most strongly between adult-onset disorders (bipolar and major depressive disorder, and schizophrenia). Further pathway analysis corroborated that calcium channel activity could play an important role in the development of all five disorders.

“This analysis provides the first genome-wide evidence that individual and aggregate molecular genetic risk factors are shared between five childhood-onset or adult-onset psychiatric disorders that are treated as distinct categories in clinical practice,” says Jordan Smoller, M.D., director of the Psychiatric and Neurodevelopmental Genetics Unit at Massachusetts General Hospital, one of the lead researchers.

Writing in a linked comment, Alessandro Serretti and Chiara Fabbri from the University of Bologna in Italy say, “the present study might contribute to future nosographic [classification] systems, which could be based not only on statistically determined clinical categories, but also on biological pathogenic factors that are pivotal to the identification of suitable treatments.

“Genetics…can contribute to prediction and prevention of psychiatric diseases, along with the identification of molecular targets for new generations of psychotropic drugs,” they add.

The study is published today, Online First in The Lancet. The paper is called “Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis”. The corresponding comment is titled “Shared genetics among major psychiatric disorders”.